Laminated drug-polymer coated stent having dipped layers

ABSTRACT

The present invention provides a method of applying a drug-polymer coating on a stent. A stent framework is dipped into a first polymeric solution including a first polymer, a first therapeutic agent, and a first solvent. The polymeric solution is dried to form a thin drug-polymer layer on the stent framework. The stent framework with the thin drug-polymer layer, which is insoluble in the second polymeric solution, is dipped into a second polymeric solution including a second polymer and a second solvent and is dried to form a thin barrier layer on the thin drug-polymer layer. The steps of dipping the stent framework into the first polymeric solution, drying the first polymeric solution, dipping the stent framework into the second polymeric solution, and drying the second polymeric solution are repeated until a target drug-polymer coating thickness is disposed on the stent framework.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. provisional patentapplication Ser. No. 60/485,766, filed Jul. 9, 2003, the contents ofwhich are hereby incorporated by reference.

FIELD OF THE INVENTION

This invention relates generally to biomedical stents. Morespecifically, the invention relates to a laminated drug-polymer coatingdisposed on an endovascular stent for in vivo, time-release drugdelivery, and methods of coating thereof.

BACKGROUND OF THE INVENTION

Endovascular stents have become increasingly important in medicalprocedures to restore the function of bodily lumens. With generally opentubular structures, the stents typically have apertured or lattice-likewalls of a metallic or polymeric base, and can be either balloonexpandable or self-expanding. A stent is typically deployed by mountingthe stent on a balloon portion of a balloon catheter, positioning thestent in a body lumen, and expanding the stent by inflating the balloon.The balloon is then deflated and removed, leaving the stent in place.Stents help reduce the probability and degree of vessel blockage fromrestenosis.

An increasing number of stents for treating vascular conditions arebeing coated with protective materials and bioactive drugs. A variety ofstent coatings and compositions have been proposed to provide localizedtherapeutic pharmacological agents and treatment of a vessel at the sitebeing supported by the stent. Stent coatings with various families ofdrug polymer chemistries have been used to increase the effectiveness ofstenting procedures and to control drug-elution properties. For example,polymeric coatings can be made from polyurethane, polyester, polylacticacid, polyamino acid, polyorthoester, and polyphosphate ester. Examplesof drug or bioactive agents include antirestonotic and anti-inflammatorycompounds.

Medical research indicates a greater effectiveness of vascular stentswhen stents are coated with pharmaceutical drugs that help prevent ortreat medical conditions such as restenosis and thrombosis. These drugsmay be released from a coating while in the body, delivering theirpatent effects at the site where they are most needed. The localizedlevels of the medications can be elevated, and are therefore potentiallymore effective than orally or intravenously delivered drugs.Furthermore, drugs released from tailored stent coatings can havecontrolled, timed-release qualities, eluting their bioactive agents overhours, weeks or even months. Stent coatings typically have a drug oractive agent, which has been dissolved or dispersed throughout thepolymeric material and physically constrained within the polymer. Thesustained release of drugs generally relies upon either degradation ofthe polymer or diffusion through the polymer to control the elution ofthe compounds.

Drug polymer coatings on medical devices such as stents and cathetersneed to be mechanically pliant because the devices undergo significantflexion or expansion during the delivery and deployment. A stentdeployed by self-expansion or balloon expansion is accompanied by a highlevel of bending at portions of the stent framework, which can causecracking, flaking, peeling, or delaminating of many candidate drugpolymers when the stent diameter is increased by threefold or moreduring expansion. In addition, any step within the process for coating apre-deployed stent should not cause a drug-polymer to fall off,crystallize or melt. Chudzik et al. disclose a flexible coatingcomposition to address the need for pliancy in “Bioactive Agent ReleaseCoating”, U.S. Pat. No. 6,344,035 issued Feb. 5, 2002. The bioactiveagent or drug is in combination with a mixture of polymers such aspoly(butyl methacrylate) and poly(ethylene-co-vinyl acetate). Polymersfor use as stent coatings need to demonstrate characteristics ofbiocompatibility, good drug release as well as flexibility.

In selecting polymers for drug delivery and applying drug coatings tostents, certain criteria must be met: polymer biocompatibility,satisfactory mechanical properties such as durability and integrityduring roll down and expansion of the stent, and correct releaseprofiles for the drugs. Candidate chemistries for drug polymers mayresult in excessively rapid elution of an incorporated drug. When a drugis eluted too quickly, it may be ineffective and may fail to achieve thedesired effect in the surrounding tissue bed. If a drug is eluted tooslowly, the pharmaceutical intent may remain unfulfilled. Furthermore,incorporation of more than one drug in the same coating can result in amuch faster elution rate than a second drug in the same drug polymer,making the controlled delivery of multiple drugs difficult. Evenpharmaceutical compounds with nearly the same pharmaceutical effect canhave dramatically different elution rates in the same coating chemistry,depending on the formation of the compounds.

Stents can be coated with a polymer or combination of a polymer and apharmaceutical agent or drug by application techniques such as dipping,spraying, painting, and brushing. In many of the current medical deviceor stent coating methods, a composition of a drug and a polymer in asolvent is applied to a device to form a substantially uniform layer ofdrug and polymer. A common solvent for the polymers and drugs employedis usually required, and techniques have been developed to micronize thedrugs into small particles so that the drugs can be suspended in thepolymer solution. Micronization can be time consuming, and may result ina degradation or loss of desired therapeutic properties of the drug. Amethod of using micronized drugs and layering a drug-coated stent usingpharmacological and polymeric agents is described by Guruwaiya et al. inU.S. Pat. No. 6,251,136 issued Jun. 26, 2001. A pharmacological agent isapplied to a stent in dry, micronized form over a sticky base coating. Amembrane-forming polymer, selected for its ability to allow thediffusion of the pharmacological agent therethrough, is applied over theentire stent. More specifically, a stent, typically a metal stent, has alayer of a sticky material applied to selected surfaces of the stent. Apharmacological agent is layered on the sticky material and a membraneforming a polymer coating is applied over the pharmacological agent. Themembrane is formed from a polymer that permits diffusion of thepharmacological agent over a predetermined time period.

A method of applying drug-release polymer coatings that uses solvents isdescribed in “Method of Applying Drug-Release Coatings”, Ding et al.,U.S. Pat. No. 5,980,972 issued Nov. 9, 1999. A polymer is dissolved inone solvent and a drug is dissolved or suspended in a similar ordifferent type of solvent. The solutions are applied either sequentiallyor simultaneously onto the devices by spraying or dipping to form asubstantially homogenous composite layer of the polymer and thebiologically active material.

Many of the drug-coated stents in recent years have been sprayed withrather than dipped in a drug-polymer solution. Spray coating, acurrently preferred method for coating stents, can result in asignificant amount of spray material lost during the process and whenexpensive drugs are used in these coatings, the use of spray coating maybe costly.

Dip coating was used with early stents and other medical-device designsthat were of relatively open construction fabricated from wires or fromribbons. Dipped coatings with relatively low coating weights, forexample, coatings with about 4% polymer, were used with some occurrencesof bridging or webbing of the coating in the open spaces or slotsbetween the structural members of the device. Such coating methods wereperformed by manually dipping the stent in a liquid, and then removingthe stent and drying it. The dipping process requires care to avoidexcess liquid on the stent framework or inconsistent drying of theliquid, otherwise the apertures can become blocked unnecessarily.Applying a thick coating tends to exacerbate webbing and bridgingproblems, and increasing the solids content of the coating solution alsoincreases webbing and bridging between the struts. Any coating methodneeds to avoid webbing, as well as control the weight and thickness of acoating.

Problems of webbing and having excess coating material on stent strutsare recognized by those skilled in the art of manufacturing stents. Forexample, a manual-dipping process step that blows excess material offthe open framework of a tubular stent is disclosed in “Coating” byTaylor et al., U.S. Pat. No. 6,214,115 issued Apr. 10, 2001. The processaddresses the problems of inconsistent drying and blockage of openings.Another dipping process that addresses the issues of blockage andbridging between the stent struts is disclosed by Hossainy et al. in“Process for Coating Stents”, U.S. Pat. No. 6,153,252 issued Nov. 28,2000. Flow or movement of the coating fluid through the openings in theperforated medical device is used to avoid the formation of blockages orbridges. The flow system may use a perforated manifold inserted in thestent to circulate the coating fluid, or may place the stent on amandrel or in a small tube that is moved relative to the stent duringthe coating process.

Newer stents that are of less open construction, such ascatheter-deployed, self-expanding stents are more difficult to coatevenly using a dipping method. Nevertheless, one advantage of dipcoating is the ability to process a greater number of stents in a moreefficient manufacturing process.

A stent with a single coating having at least one therapeutic agent isdescribed by Sirhan and Yan in “Delivery or Therapeutic Capable Agents”,U.S. Patent Application No. 20020082679 published Jun. 27, 2002. Barryand others describe another polymer composition that can be used fordelivering substantially water-insoluble drugs in “Loading and Releaseof Water-Insoluble Drugs”, U.S. Pat. No. 6,306,166 issued Oct. 23, 2001.A medical device is coated with one or more layers of a volatile organicsolution comprising a polyvinyl aromatic polymer and an antineoplasticchemotherapy drug such as paclitaxel. In the descriptions of theaforementioned coatings, dipping is given as one of the methods forapplying the drug-polymer coating to the device, although thedisclosures do not address the potential problem of webbing or bridgingin the open areas of stent structures, particularly when multiple coatsare applied.

Jayaraman proposes a solution to the webbing or bridging issue in“Process for Coating a Surface of a Stent”, U.S. Pat. No. 6,517,889issued Feb. 11, 2003. The coating process includes inserting a threadthrough the lumen of the stent and producing relative motion between thestent and the thread to remove coating material located within theopenings of the stent.

Multiple dips can be used to build up the weight and thickness of thecoating, but each subsequent dip may affect the coating alreadydeposited. A coating can re-dissolve in a second coating solution,causing some loss of the first layer of coating. Also, applications ofmultiple dip coats from low concentration solutions can have the effectof reaching a limiting loading level as equilibrium is reached betweenthe solution concentration and the amount of coating with or without apharmaceutical agent. One such method that applies a plurality ofrelatively thin coatings on an open-lattice stent is disclosed in “DrugRelease Stent Coating”, Ding et al., U.S. Pat. No. 6,358,556 issued Mar.19, 2002. The stents are coated by dipping or preferably spraying thestent with a solvent mixture of uncured polymeric silicone material witha crosslinker and a finely divided biologically active species. Themethod includes a step for sterilizing with an inert argon gas plasmaand exposure to gamma radiation. Potential problems with bridging orwebbing in the lattice framework are not addressed.

Accordingly, what is needed is a more efficient manufacturing method forcoating medical devices such as stents that can apply drug-polymercoatings without creating undesirable bridging or webbing. An improvedprocess provides coatings that are well adhered and flexible, a well ascontrols coating properties such as thickness, porosity, and smoothness.An improved stent with one or more drug-polymer coatings maintainsmechanical integrity during its deployment, provides a desired elutionrate for one or more drugs, and overcomes the deficiencies andlimitations described above.

SUMMARY OF THE INVENTION

One aspect of the invention provides a method of applying a drug-polymercoating on a stent. A stent framework is dipped into a first polymericsolution comprising a first polymer, a first therapeutic agent, and afirst solvent. The first polymeric solution is dried to form a thindrug-polymer layer on the stent framework. The stent framework includingthe thin drug-polymer layer is dipped into a second polymeric solutioncomprising a second polymer and a second solvent. The second polymericsolution is dried to form a thin barrier layer on the thin drug-polymerlayer. The thin drug-polymer layer is insoluble in the second polymericsolution. The dipping and drying steps are repeated until a targetdrug-polymer coating thickness is disposed on the stent framework.

Another aspect of the invention provides a drug-polymer coated stentincluding a stent framework and a laminated drug-polymer coatingdisposed on the stent framework. The laminated drug-polymer coatingincludes a plurality of thin drug-polymer layers positioned between thinbarrier layers. The thin drug-polymer layers include a first therapeuticagent and a first polymer. The thin barrier layers include a secondpolymer.

Another aspect of the invention is a system for treating a vascularcondition, including a catheter and a coated stent coupled to thecatheter. The coated stent includes a stent framework and a laminateddrug-polymer coating disposed on the stent framework. The laminateddrug-polymer coating has a plurality of thin drug-polymer layersincluding a first therapeutic agent and a first polymer positionedbetween thin barrier layers that include a second polymer.

Another aspect of the invention is a method of treating a vascularcondition. A drug-polymer coated stent, which is inserted within avessel of a body, includes a laminated drug-polymer coating having thindrug-polymer layers with a therapeutic agent and a first polymer, andthin barrier layers with a second polymer. At least one therapeuticagent is eluted from the laminated drug-polymer coating into the body.

The present invention is illustrated by the accompanying drawings ofvarious embodiments and the detailed description given below. Thedrawings should not be taken to limit the invention to the specificembodiments, but are for explanation and understanding. The detaileddescription and drawings are merely illustrative of the invention ratherthan limiting, the scope of the invention being defined by the appendedclaims and equivalents thereof. The foregoing aspects and otherattendant advantages of the present invention will become more readilyappreciated by the detailed description taken in conjunction with theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments of the present invention are illustrated by theaccompanying figures, wherein:

FIG. 1 is an illustration of a system for treating a vascular conditionincluding a drug-polymer coated stent coupled to a catheter, inaccordance with one embodiment of the current invention;

FIG. 2 is a cross-sectional perspective view of a drug-polymer coatedstent, in accordance with one embodiment of the current invention;

FIG. 3 is an illustration of a system for applying a drug-polymercoating on a stent, in accordance with one embodiment of the currentinvention;

FIG. 4 is a graph of drug concentration in a laminated drug-polymercoated stent, in accordance with one embodiment of the currentinvention;

FIG. 5 is a graph of drug elution rate from a drug-polymer coated stent,in accordance with one embodiment of the current invention;

FIG. 6 is a flow diagram of a method of applying a drug-polymer coatingon a stent, in accordance with one embodiment of the current invention;and

FIG. 7 is a flow diagram of a method for treating a vascular condition,in accordance with one embodiment of the current invention.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS

FIG. 1 shows an illustration of a system for treating a vascularcondition, comprising a drug-polymer coated stent coupled to a catheter,in accordance with one embodiment of the present invention at 100.Coated stent with catheter 100 includes a drug-polymer coated stent 120coupled to a delivery catheter 110. Drug-polymer coated stent 120includes a stent framework 130 and a laminated drug-polymer coating 140disposed on the stent framework. Laminated drug-polymer coating 140includes a plurality of thin drug-polymer layers positioned between thinbarrier layers. The drug-polymer layers include a therapeutic agent anda first polymer. The barrier layers include a second polymer that mayalso include a second therapeutic agent. The constituents ofdrug-polymer coated stent 120 are selected to minimize leaching of drugor polymer from underlying layers when forming the multi-layerdip-coated stent.

Insertion of coated stent 120 into a vessel in the body helps treat, forexample, heart disease, various cardiovascular ailments, and othervascular conditions. Catheter-deployed coated stent 120 typically isused to treat one or more blockages, occlusions, stenoses, or diseasedregions in the coronary artery, femoral artery, peripheral arteries, andother arteries in the body. Treatment of vascular conditions may includethe prevention or correction of various ailments and deficienciesassociated with the cardiovascular system, the cerebrovascular system,urinogenital systems, biliary conduits, abdominal passageways and otherbiological vessels within the body.

An exemplary laminated drug-polymer coating 140 includes or encapsulatesone or more therapeutic agents. Laminated drug-polymer coating 140 maycomprise one or more therapeutic agents dispersed within or encased bydrug-polymer layers or barrier layers on coated stent 120, which areeluted from coated stent 120 with controlled time delivery afterdeployment of coated stent 120 into the body. A therapeutic agent iscapable of producing a beneficial effect against one or more conditionsincluding coronary restenosis, cardiovascular restenosis, angiographicrestenosis, arteriosclerosis, hyperplasia, and other diseases orconditions. For example, the therapeutic agent can be selected toinhibit or prevent vascular restenosis, a condition corresponding to anarrowing or constriction of the diameter of the bodily lumen where thestent is placed. Laminated drug-polymer coating 140 may comprise, forexample, an antirestenotic agent such as rapamycin, a rapamycinderivative, or a rapamycin analog to prevent or reduce the recurrence ofnarrowing and blockage of the bodily vessel. Laminated drug-polymercoating 140 may comprise an anti-cancer drug such as camptothecin orother topoisomerase inhibitors, an antisense agent, an antineoplasticagent, an antiproliferative agent, an antithrombogenic agent, ananticoagulant, an antiplatelet agent, an antibiotic, ananti-inflammatory agent, a steroid, a gene therapy agent, an organicdrug, a pharmaceutical compound, a recombinant DNA product, arecombinant RNA product, a collagen, a collagenic derivative, a protein,a protein analog, a saccharide, a saccharide derivative, a bioactiveagent, a pharmaceutical drug, a therapeutic substance, or a combinationthereof.

The elution rates of the therapeutic agents and total drug eluted intothe body and the tissue bed surrounding the stent framework are based onthe target thickness of laminated drug-polymer coating 140, theconstituency and individual layer thicknesses of laminated drug-polymercoating 140, the nature and concentration of the therapeutic agents, thethickness and composition of any cap coat, and other factors. Laminateddrug-polymer coating 140 may include and elute multiple therapeuticagents to achieve the desired therapeutic effect. Laminated drug-polymercoating 140 can be tailored to control the elution of one or moretherapeutic agents primarily by diffusion processes. In some cases, aportion of the polymeric coating is absorbed into the body, releasingtherapeutic agents from within the coating. The barrier layers can beselected to provide a diffusion barrier to the therapeutic agents andslow drug elution.

Incorporation of a drug or other therapeutic agent into laminateddrug-polymer coating 140 allows, for example, the rapid delivery of apharmacologically active drug or bioactive agent within twenty-fourhours following the deployment of a stent, with a slower, steadydelivery of a second bioactive agent over the next three to six months.In one example, a first therapeutic agent comprises an antirestenoticdrug such as rapamycin, a rapamycin derivative, or a rapamycin analog.The second therapeutic agent may comprise, for example, an anti-cancerdrug such as camptothecin or other topoisomerase inhibitors. Thetherapeutic agent constituency in the drug-polymer layers may be, forexample, between 0.1 percent and 50 percent of the drug-polymer layer byweight. In another example, the first therapeutic agent comprises ananti-proliferative compound such as 5-fluorouracil, with an optionalsecond therapeutic agent such as rapamycin, a rapamycin derivative, arapamycin analog, or dexamethosone. In another example, the firsttherapeutic agent comprises an anti-inflammatant such as dexamethasone,and an optional second therapeutic agent such as 5-fluorouracil.

Catheter 110 of an exemplary embodiment of the present inventionincludes a balloon 112 that expands and deploys the stent within avessel of the body. After positioning coated stent 120 within the vesselwith the assistance of a guide wire traversing through a guidewire lumen114 inside catheter 110, balloon 112 is inflated by pressurizing a fluidsuch as a contrast fluid that fills a tube inside catheter 110 andballoon 112. Coated stent 120 is expanded until a desired diameter isreached, and then the contrast fluid is depressurized or pumped out,separating balloon 112 from coated stent 120 and leaving coated stent120 deployed in the vessel of the body. Alternately, catheter 110 mayinclude a sheath that retracts to allow expansion of a self-expandingversion of coated stent 120.

FIG. 2 shows a cross-sectional perspective view of a drug-polymer coatedstent, in accordance with one embodiment of the present invention at200. A drug-polymer coated stent 220 includes a stent framework 230 witha laminated drug-polymer coating 240 disposed on stent framework 230.Laminated drug-polymer coating 240 includes a plurality of thindrug-polymer layers 242 and 246 that are positioned between thin barrierlayers 244 and 248. Drug-polymer layers 242 and 246 include acombination or mixture of a first therapeutic agent and a first polymer,and barrier layers 244 and 248 include a second polymer.

Although illustrated with two sets of drug-polymer layers and barrierlayers, multiple sets of coating layers may be disposed on stentframework 230. For example, ten sets of layers, each layer on the orderof 0.1 micrometers thick, can be alternately disposed on stent framework230 to produce a two-micrometer thick coating. In another example,twenty sets of layers, each layer on the order of 0.5 micrometers thick,can be alternately disposed on stent framework 230 to produce atwenty-micrometer thick coating. The drug-polymer layers and the barrierlayers need not be the same thickness, and the thickness of each may bevaried throughout laminated drug-polymer coating 240. Alternately, thefirst coating layer may be a barrier layer, and the final coating layermay comprise, for example, a thick cap coat.

Stent framework 230 comprises a metallic base or a polymeric base, suchas stainless steel, nitinol, tantalum, MP35N alloy, platinum, titanium,a chromium-based alloy, a suitable biocompatible alloy, a suitablebiocompatible material, a biocompatible polymer, or a combinationthereof. The polymeric base material may comprise any suitable polymerfor biomedical stent applications, as is known in the art.

In one example, drug-polymer layers 242 and 246 comprise a first polymersuch as poly(ethylene-vinyl acetate) (PEVA) and a first therapeuticagent such as camptothecin, rapamycin, a rapamycin derivative, or arapamycin analog. Barrier layers 244 and 248 comprise a second polymersuch as polyurethane, polycaprolactone, or a blended polymer ofpolyurethane and polycaprolactone that can be selected based on apredetermined elution rate. For example, tailoring the fraction of thetwo polymers, the thickness of the drug-polymer layers and the barrierlayers, or the concentration of the therapeutic agents controls theelution rate of one or more therapeutic agents dispersed within orencased by laminated drug-polymer coating 240. Drug elution refers tothe transfer of a therapeutic agent from laminated drug-polymer coating240 to the surrounding area in a body. The amount of drug eluted isdetermined as the total amount of therapeutic agent excreted out oflaminated drug-polymer coating 240, typically measured in units ofweight such as micrograms, or in weight per peripheral area of thestent. In another embodiment, barrier layers 244 and 248 include asecond therapeutic agent such as camptothecin. In another embodiment,the concentration of the therapeutic agents in either drug-polymerlayers 242 and 246 or barrier layers 244 and 248 are modulated toprovide a predetermined drug-release profile. The concentration of thesecond therapeutic agent in barrier layers 244 and 248 may be between,for example, 0.1 percent and 50 percent by weight.

In another example of a multi-layer coated stent, drug-polymer layers242 and 246 comprise a first polymer including a rigid thermoplasticpolyurethane and an anti-proliferative therapeutic agent such as5-fluorouracil, and barrier layers 244 and 248 include an ester-extendedpolyurethane. An example of a rigid thermoplastic polyurethane isTECOPLAST®, a hydrophobic polymer available from Thermedics PolymerProducts in Wilmington, Mass. An example of an ester-extendedpolyurethane is TECOPHILIC®, a hydrophilic polymer also available fromThermedics Polymer Products in Wilmington, Mass. Barrier layers 244 and248 may optionally include a therapeutic agent such as rapamycin, arapamycin derivative, or a rapamycin analog. Alternatively, barrierlayers 244 and 248 may include an anti-inflammatant such asdexamethasone.

In another example, drug-polymer layers 242 and 246 comprise a firstpolymer including a copolymer of methacrylamide, methacrylate, and vinylalcohol with an anti-proliferative therapeutic agent such as5-fluorouracil. Barrier layers 244 and 248 include a second polymer suchas rigid thermoplastic polyurethane and may include an anti-inflammatantsuch as dexamethasone.

In another example, drug-polymer layers 242 and 246 comprise a firstpolymer including a copolymer of methacrylamide, methacrylate, and vinylacetate with an anti-inflammatant such as dexamethasone. Barrier layers244 and 248 include a second polymer such as poly(butyl methacrylate)(PBMA), and may include a second therapeutic agent such as5-fluorouracil.

FIG. 3 shows an illustration of a system for applying a drug-polymercoating on a stent, in accordance with one embodiment of the currentinvention at 300. Drug-polymer coating system 300 includes a firstpolymeric solution 350 in a first tank 352, a second polymeric solution360 in a second tank 362, and a mechanism 322 such as a mandrel, aclamp, or a tether for holding and transporting stents in and out of atank either manually or automatically. Multiple stent frameworks 330 arereadily accommodated for dipping and drying in a batch or continuousbatch process.

First polymeric solution 350 includes a first polymer 354, a firsttherapeutic agent 356, and a first solvent 358. Stent framework 330 canbe dipped into first polymeric solution 350 and dried, for example, bypositioning dipped stent framework 330 in air or in an oven andevaporating first solvent 358 to form a thin drug-polymer layer.Minimizing the solids content of first polymeric solution 350 can lowerthe viscosity, so that uniform coating and minimal or no bridging occursacross the apertures of stent framework 330.

Second polymeric solution 360 includes a second polymer 364 and a secondsolvent 368. Stent framework 330 with the first laminated drug-polymerlayer can be dipped into second polymeric solution 360 and dried, forexample, by positioning dipped stent framework 330 in an oven or in airfor high throughput and evaporating second solvent 368 to form a thinbarrier layer. Second polymeric solution 360 may include a secondtherapeutic agent 366 dissolved into second solvent 368. Low viscosityfor minimizing bridging and webbing across the apertures of stentframework 330 can be obtained by minimizing the solids content of secondpolymeric solution 360.

A third polymeric solution 370 in a third tank 372 with a third polymer374 and a third solvent 378 may be included with drug-polymer coatingsystem 300. Third polymeric solution 370 may include a third therapeuticagent 376 dissolved in third solvent 378. In one example, third polymer374 is the same as first polymer 354, third solvent 378 is the same asfirst solvent 358, and third therapeutic agent 376 is the same as firsttherapeutic agent 356, though at a higher or a lower concentration thanfirst therapeutic agent 356 in first polymeric solution 350. In thiscase, the concentration of third therapeutic agent 376 disposed on stentframework 330 can be higher or lower than previously dipped and drieddrug-polymer layers. The concentration of first therapeutic agent 356 inthe drug-polymer layers can be modulated to provide a predetermineddrug-release profile.

In another example, third polymer 374 is the same as second polymer 364,third solvent 378 the same as second solvent 368, and third therapeuticagent 376 is the same as second therapeutic agent 366 though at a higheror a lower concentration than second therapeutic agent 366 in secondpolymeric solution 360. The concentration of third therapeutic agent 376disposed on stent framework 330 can be higher or lower than previouslydipped and dried barrier layers, so that the concentration of secondtherapeutic agent 366 in the barrier layers can be modulated to providea predetermined drug-release profile for second therapeutic agent 366from a coated stent when deployed in a body.

In other examples, the concentrations of third polymer 374 in thirdpolymeric solution 370 can be varied to adjust the viscosity, solidscontent, and subsequent thickness of drug-polymer layers or barrierlayers within a drug-polymer coated stent, so that a predetermineddrug-release profile of one or more therapeutic agents in thedrug-polymer layers or the barrier layers can be provided.

FIG. 4 shows a graph of drug concentration in a laminated drug-polymercoated stent, in accordance with one embodiment of the present inventionat 400. An exemplary coated stent has a laminated drug-polymer coatingwith a plurality of thin drug-polymer layers positioned between thinbarrier layers. The drug-polymer layers include a therapeutic agent anda first polymer, and the barrier layers include a second polymer. Thebarrier layers may include a second therapeutic agent.

The laminated drug-polymer coatings on the coated stent elute at leastone therapeutic agent. Alternatively, the laminated drug-polymer coatingmay include and elute multiple therapeutic agents. The thickness of theindividual layers, the types of polymers selected, and the concentrationof the therapeutic agents, among other factors, can be tailored tocontrol the elution of one or more therapeutic agents from the coatedstent. Elution of therapeutic agents occurs primarily by diffusionprocesses. In some cases, a portion of the laminated drug-polymercoating is absorbed into the body to release the therapeutic agents. Inother cases, a portion of polymeric coating erodes away to release thetherapeutic agents.

In this exemplary embodiment, a plurality of drug-polymer layers 480,482 and 484 include a first therapeutic agent with a modulatedconcentration to provide a predetermined drug-release profile, and aplurality of thin barrier layers 490, 492 and 494 include a secondtherapeutic agent with a modulated concentration. Drug-polymer layersclose to the stent framework, in this example, have a higherconcentration of the first therapeutic agent than drug-polymer layersnear the outside of the laminated drug-polymer coating. Barrier layersclose to the stent framework have a lower concentration of the secondtherapeutic agent than barrier layers near the outside of the laminateddrug-polymer coating. In another embodiment, the barrier layers containno therapeutic agents. In other embodiments, the concentrations of thefirst therapeutic agents and the second therapeutics along with thethickness of the drug-polymer layers and the barrier layers are variedto achieve a predetermined drug-release profile for each of thetherapeutic agents.

FIG. 5 shows a graph of drug elution rate from a drug-polymer coatedstent, in accordance with one embodiment of the present invention at500. Drug elution rate graph 500 shows a characteristic curve 586representing the elution of a first therapeutic agent into the bodyafter the coated stent is deployed. After deployment into the body, thefirst therapeutic agent is eluted from the laminated drug-polymercoating in a predetermined profile, with a small amount of the firsttherapeutic agent released within the first several days, and increasingto a higher delivery rate in a following period of weeks or months untilthe therapeutic agent is completely eluted. The elution rate may bedetermined from a graph that represents the total drug eluted by takingthe derivative with respect to time, or by dividing the amount of drugeluted over a specified time interval by the elapsed time.

Drug elution rate graph 500 also shows a characteristic curve 596representing the elution of a second therapeutic agent into the body.After deployment into the body, the second therapeutic agent is elutedfrom the laminated drug-polymer coating in a predetermined profile, witha large amount of the second therapeutic agent released within the firstfew hours and days, and then the rate of release rapidly falling offafter that.

An elution rate for each therapeutic agent can be predetermined by acareful selection of the concentration of each therapeutic agent in thethin drug-polymer layers and the thin barrier layers; the thickness ofthe individual drug-polymer layers and the barrier layers; the polymersand polymeric blend in the drug-polymer layers and the barrier layers;and the total number of layers.

FIG. 6 shows a flow diagram of a method of applying a drug-polymercoating on a stent, in accordance with one embodiment of the presentinvention at 600. Drug-polymer application method 600 includes varioussteps to form a laminated drug-polymer coating on a stent framework, andto provide a predetermined drug-release profile when the coated stent isdeployed in the body.

A stent framework is cleaned, as seen at block 605. The stent frameworkmay be cleaned, for example, by inserting the stent framework intovarious solvents, degreasers and cleansers to remove any debris,residues, or unwanted materials from the surface of the stent framework.The stent framework is dried, and generally inspected at this point inthe process.

After cleaning, a primer coating may be disposed on the stent framework,particularly to metallic stent frameworks such as stainless steel,assisting in the adhesion of the laminated drug-polymer coating to thestent framework. The primer coating may include, for example, theapplication of a suitable primer layer such as parylene, polyurethane,phenoxy, epoxy, polyimide, polysulfone, or pellathane. The primercoating may be applied to the stent framework by dipping, spraying,painting, brushing, or other suitable methods. The primer coating isdried and cured or cross-linked as needed for eliminating or removingany volatile components. Excess liquid may be blown off prior to dryingthe primer coating, which may be done at room temperature or elevatedtemperatures under a dry nitrogen or other suitable environmentincluding a vacuum environment.

The stent framework is dipped into a first polymeric solution, as seenat block 610. The first polymeric solution comprises a first polymer, afirst therapeutic agent, and a first solvent. One or more therapeuticagents may be mixed with the first polymeric solution prior to itsapplication onto the stent framework. The mixture can be created byadding the therapeutic agents directly into the first polymericsolution. Alternatively, the mixtures can be created by dissolving thetherapeutic agents in a therapeutic agent solution comprising a suitablesolvent, and then adding and mixing them with the polymeric solution.

In one example, the first polymer of poly(ethylene-vinyl acetate)(PEVA), and the first therapeutic agent of camptothecin are dissolved ina first solvent that includes a mixture of chloroform and methanol. Thecamptothecin is dissolvable in other solvents such as a mixture ofethanol, chloroform and methanol. The first polymeric solution maycomprise, for example, between 0.05 percent and 3.0 percent and up to 10percent or more total solids by weight of the first polymer, selected toprovide a low-viscosity solution so that very thin layers of the polymerand therapeutic agent may be disposed on the stent framework that canavoid webbing and bridging between the openings in the stent framework.In another example, the first therapeutic agent comprises rapamycin, arapamycin derivative, or a rapamycin analog. In a currently preferredembodiment, the solvent has a chloroform concentration between 80percent and 90 percent, with methanol comprising the balance. Therapamycin and associated compounds are soluble in other solvents, suchas acetones, heptanes, methyl tertiary-butyl ether (MTBE), methylenechloride (MEC), tetrahydrofuran (THF), and isopropyl alcohol.

In another example, the first polymeric solution includes a rigidthermoplastic polyurethane and a therapeutic agent such as5-fluorouracil in a blend of tetrafuran and methanol. The concentrationof total solids by weight of the first polymer in the solvent rangesbetween 0.05 percent and 10.0 percent, with a presently preferred rangebetween 0.1 percent and 3.0 percent. The concentration of thetherapeutic agent in the dried layer may range between 0.1 percent and50 percent or greater. The concentration of tetrahydrofuran in thesolvent may range between 10 percent and 90 percent or greater, with apresently preferred concentration of 80 percent tetrahydrofuran andmethanol comprising the balance.

In another example, a copolymer of methacrylamide, methacrylate andvinyl alcohol are mixed with 5-fluorouracil in chloroform and water. Inanother example, a copolymer of methacrylamide, methacrylate and vinylacetate are mixed with dexamethasone in ethanol.

The first polymeric solution is dried to form a thin drug-polymer layeron the stent framework, as seen at block 615. The dipped stent frameworkmay be dried, for example, by positioning the dipped stent framework inair after dipping the stent framework into the first polymeric solution,and evaporating the first solvent prior to dipping the stent frameworkin the next polymeric solution. The first polymeric solution isgenerally dried after application by evaporating off the solvent at roomtemperature and under ambient conditions. A nitrogen environment orother controlled environment may also be used for drying. Alternatively,the first polymeric solution can be dried by evaporating the majority ofthe solvent at room temperature, and then further dried in a vacuumenvironment between, for example, a room temperature of about 25 degreescentigrade and 45 degrees centigrade or higher to extract any pockets ofsolvent buried within the drug-polymer layer. Vacuum drying, heatedconvective air, forced air or hot air, heated convective nitrogen,forced nitrogen or forced heated nitrogen or other suitable dryingmethods and combinations thereof for full or partial drying may be used.

The stent framework including the drug-polymer layer is dipped into asecond polymeric solution, as seen at block 620. The second polymericsolution includes a second polymer and a second solvent, the secondsolvent selected so that the drug-polymer layer dried on the stentframework is insoluble in the second polymeric solution. The polymersand therapeutic agents in the drug-polymer layers and the thin barrierlayers may be selected to be marginally soluble or insoluble in therespective solvents that are used.

The second polymer may be selected, for example, with a low glasstemperature and a low affinity for the drugs or therapeutic agents inthe drug-polymer layer. The second polymeric solution may comprise, forexample, between 0.05 percent and 3.0 percent and up to 10.0 percent ormore total solids by weight of the second polymer, selected to provide alow-viscosity solution so that thin barrier layers of the second polymermay be disposed on the stent framework. The stent framework with thefirst drug-polymer layer can be dipped into the second polymer solutionwithout impacting the content of the initial layer. In one example, thesecond polymer comprises polyurethane. In another example, the secondpolymer comprises polycaprolactone. In another example, the secondpolymer comprises a blended polymer of polyurethane andpolycaprolactone. The second solvent comprises, for example,tetrahydrofuran. The second polymeric solution may comprise a secondtherapeutic agent such as camptothecin mixed into or added to the secondpolymeric solution.

In another example, the second polymeric solution includes anester-extended polyurethane mixed in chloroform. Optionally, ananti-proliferative compound such as rapamycin, a rapamycin derivative,or a rapamycin analog may be mixed into the second polymeric solution.Alternatively, dexamethasone or other anti-inflammatant may be mixedinto the second polymeric solution. The concentration of the polymers inthe solvent may range, for example, between 0.05 percent and 3.0 percentand up to 10.0 percent or more. The concentration of the rapamycin,rapamycin derivative or rapamycin analog ranges, for example, between0.1 percent and 50 percent by weight in the dried layer.

In another example, the second polymeric solution includes a rigidthermoplastic polyurethane dissolved in tetrahydrofuran. Ananti-inflammatant such as dexamethasone may optionally be mixed into thesolution.

In another example, the second polymeric solution includes poly(butylmethacrylate) dissolved in a blend of tetrahydrofuran and methanol. Ananti-proliferative compound such as 5-fluorouracil may optionally bemixed into the solution.

The second polymeric solution is dried to form a thin barrier layer onthe stent framework, as seen at block 625. The barrier layer issubstantially insoluble in the first polymeric solution, so that whensubsequent layers of drug-polymer layers are formed on the stentframework, underlying barrier layers are neither dissolved nor erodedaway. The barrier layer may be selected to provide a diffusion barrierto the drug in the drug-polymer layer and slow down drug elution.

After the stent framework has been dipped into the second polymericsolution, the second polymeric solution may be dried, for example, in anoven at an elevated temperature, or by positioning the dipped stentframework in air at room temperature, and evaporating the second solventprior to dipping the framework into the next polymeric solution. Vacuumdrying, heated convective air, forced air or hot air, heated convectivenitrogen, forced nitrogen or forced heated nitrogen or other suitabledrying methods and combinations thereof for full or partial drying maybe used.

The steps of dipping the stent framework into the first polymericsolution, drying the first polymeric solution, dipping the stentframework into the second polymeric solution, and drying the secondpolymeric solution are repeated until a target drug-polymer coatingthickness is disposed on the stent framework, as seen at block 630.Multiple dipping and drying steps are used to provide an appropriatecoating weight and avoid webbing or bridging of the apertures betweenthe struts in the stent framework. Repeatedly applying thin drug-barrierlayers and thin barrier layers allows for uniform, defect-freedip-coated items. The concentration of the first therapeutic agent inthe first polymeric solution may be changed between the dipping anddrying steps to modulate the concentration of the first therapeuticagent in the drug-polymer layers and provide a predetermineddrug-release profile. The concentration of the second therapeutic agentin the second polymeric solution, when used, may also be changed betweendipping and drying steps, providing a different concentration of thesecond therapeutic agent in the barrier layers and providing apredetermined drug-release profile. Different drug concentrations in thedrug-polymer layers can be selected to provide a tailored elution curve,and the barrier layers may help to preserve and prolong the elution ofthe drugs. The chosen composition of the thin barrier layers can behighly permeable to one or more of the therapeutic agents. For example,a second polymer with a lower or higher glass transition temperaturethan the first polymer may be selected to control the elution rate.

The coated stent with the laminated drug-polymer coating may becross-linked and sterilized as needed, as seen at block 635.Cross-linking may be done by providing additional drying cycles in air,or by heating the coated stent above a curing temperature in an ovenwith a controlled ambient such as vacuum, nitrogen, or air.Sterilization may employ, for example, gamma-ray irradiation, e-beamradiation, ethylene oxide gas, or hydrogen peroxide gas plasmasterilization techniques. With appropriate selection of the barrierlayer polymer, for example, selective cross-linking of the barrier layerpolymer may occur during sterilization while the drug-polymer layerremains unaffected. The coated stent may be packaged, shipped, andstored in a suitable package until it is used.

A delivery catheter may be coupled to the coated stent, as seen at block640. The delivery catheter may include an inflatable balloon that ispositioned between the coated stent and the catheter and used fordeploying the coated stent in the body. Alternatively, the deliverycatheter may include a sheath that retracts to deploy a self-expandingversion of the coated stent.

In one exemplary method, fully processed coated stents are reduced indiameter and placed into the distal end of the catheter to form aninterference fit, which secures the stent onto the catheter. Thecatheter with the stent may be placed in a catheter package andsterilized prior to shipping and storing. Before clinical use, the stentis sterilized by any appropriate or medically conventional means.

Alternative ordering of process steps or variants of the method forapplying a drug-polymer coating on a stent can be employed. For example,a barrier layer can be applied to the stent framework before adrug-polymer layer by dipping the framework into the second polymericsolution before dipping it into the first polymeric solution, whichcontains one of more of the therapeutic agents. Other embodiments of thepresent invention include switching the order of the drug-polymer layersand the barrier layers, dipping multiple times into the same bath tothicken a layer, dipping the coated stent into additional baths withadjusted concentrations of therapeutic agents to achieve a desiredelution profile, and adjusting the temperature of each bath.

FIG. 7 shows a flow diagram of a method for treating a vascularcondition, in accordance with one embodiment of the present invention at700. Vascular condition treatment method 700 includes steps to insert adrug-polymer coated stent within a vessel of a body and to elute atleast one therapeutic agent from the drug-polymer coated stent into thebody. One or more therapeutic agents are included or interdispersedwithin thin drug-polymer layers and thin barrier layers of the laminateddrug-polymer stent coating.

The first and second polymers and their respective concentrations areselected based on a predetermined elution rate of each therapeuticagent, as seen at block 710. The solvents and concentrations of polymersand therapeutic agents are also selected to prevent dissolution of driedpolymers and drugs of previously applied layers with subsequent dippingand drying of additional drug-polymer layers and barrier layers. Thefractional constituencies of the polymers and therapeutic agents areselected to achieve an intended pharmaceutical intent, such as apredetermined elution rate for one or more therapeutic agents within thelaminated drug-polymer coating. One or more therapeutic agents areincluded in the drug-polymer layers, and one or more therapeutic agentsmay be included in the barrier layers. The laminated drug-polymer layersand barrier layers are selected to control the elution rate of eachtherapeutic agent and the total quantity of each drug delivered.

A coated stent with a laminated drug-polymer coating is fabricated byusing selected polymers, therapeutic agents, solvents and concentrationsthereof, as seen at block 720. The laminated drug-polymer coating has aplurality of thin drug-polymer layers positioned between thin barrierlayers. The drug-polymer layers include a therapeutic agent and a firstpolymer, and the thin barrier layers include a second polymer. A primercoating may be included to improve the adhesion between the stentframework and the coating layers.

When ready for deployment, the drug-polymer coated stent with theselected polymers, therapeutic agents, solvents and concentrations isinserted into a vessel of the body, as seen at block 730. Thedrug-polymer coated stent is inserted typically in a controlledenvironment such as a catheter lab or hospital. A delivery catheter,which helps position the drug-polymer coated stent in a vessel of thebody, is typically inserted through a small incision of the leg and intothe femoral artery, and directed through the vascular system to adesired place in the vessel. Guide wires threaded through an inner lumenof the delivery catheter assist in positioning and orienting thedrug-polymer coated stent. The position of the drug-polymer coated stentmay be monitored, for example, with a fluoroscopic imaging system or anx-ray viewing system in conjunction with radiopaque markers on thecoated stent, radiopaque markers on the delivery catheter, or contrastfluid injected into an inner lumen of the delivery catheter and into aninflatable catheter balloon that is coupled to the drug-polymer coatedstent. The stent is deployed, for example, by expanding the stent with aballoon or by extracting a sheath that allows a self-expandable stent toenlarge after positioning the stent at a desired location within thebody. Before clinical use, the stent is sterilized by using conventionalmedical means.

Once deployed, the therapeutic agents in the laminated drug-polymercoating are eluted, as seen at block 740. The elution rates of theselected therapeutic agents into the body and the tissue bed surroundingthe stent framework are based on the polymers, thickness of thedrug-polymer layers and barrier layers, and the concentration of thetherapeutic agents contained therein, among other factors.

Although the present invention applies to cardiovascular andendovascular stents with timed-release therapeutic agents, the use oflaminated drug-polymer coatings may be applied to other implantable andblood-contacting biomedical devices such as coated pacemaker leads,microdelivery pumps, feeding and delivery catheters, heart valves,artificial livers and other artificial organs.

While the embodiments of the invention disclosed herein are presentlyconsidered to be preferred, various changes and modifications can bemade without departing from the spirit and scope of the invention. Thescope of the invention is indicated in the appended claims, and allchanges that come within the meaning and range of equivalents areintended to be embraced therein.

1. A method of applying a drug-polymer coating on a stent, comprising:dipping a stent framework into a first polymeric solution, wherein thefirst polymeric solution comprises a first polymer, a first therapeuticagent, and a first solvent, wherein the first polymer comprises acopolymer of methacrylamide, methacrylate and vinyl alcohol, the firsttherapeutic agent comprises 5-fluorouracil, and the first solventcomprises a mixture of chloroform and water; drying the first polymericsolution to form a thin drug-polymer layer on the stent framework;dipping the stent framework including the thin drug-polymer layer into asecond polymeric solution, wherein the second polymeric solutioncomprises a second polymer and a second solvent, wherein the thindrug-polymer layer is insoluble in the second polymeric solution, andwherein the second polymer comprises a rigid thermoplastic polyurethaneand the second solvent comprises tetrahydrofuran; drying the secondpolymeric solution to form a thin barrier layer on the first thindrug-polymer layer; and repeating the steps of dipping the stentframework into the first polymeric solution, drying the first polymericsolution, dipping the stent framework into the second polymericsolution, and drying the second polymeric solution until a targetdrug-polymer coating thickness is disposed on the stent framework. 2.The method of claim 1 wherein the first polymeric solution comprisesbetween 0.05 percent and 10.0 percent total solids by weight of thefirst polymer.
 3. The method of claim 1 wherein the second polymericsolution comprises an anti-inflammatant.
 4. The method of claim 1wherein the second polymeric solution comprises dexamethasone.
 5. Themethod of claim 1 wherein the thin barrier layer is insoluble in thefirst polymeric solution.
 6. The method of claim 1 wherein drying thefirst polymeric solution comprises positioning the dipped stentframework in air after dipping the stent framework into the firstpolymeric solution, and evaporating the first solvent.
 7. The method ofclaim 1 wherein drying the second polymeric solution comprisespositioning the dipped stent framework in air after dipping the stentframework into the second polymeric solution, and evaporating the secondsolvent.
 8. The method of claim 1 further comprising: modulating aconcentration of the first therapeutic agent in the thin drug-polymerlayers to provide a predetermined drug-release profile.
 9. A method ofapplying a drug-polymer coating on a stent, comprising: dipping a stentframework into a first polymeric solution, wherein the first polymericsolution comprises a first polymer, a first therapeutic agent, and afirst solvent, wherein the first polymer comprises a copolymer ofmethacrylamide, methacrylate and vinyl acetate; the first therapeuticagent comprises dexamethasone; and the first solvent comprises ethanol;drying the first polymeric solution to form a thin drug-polymer layer onthe stent framework; dipping the stent framework including the thindrug-polymer layer into a second polymeric solution, wherein the secondpolymeric solution comprises a second polymer and a second solvent,wherein the second polymer comprises poly(butyl methacrylate); and thesecond solvent comprises a blend of tetrahydrofuran and methanol, andwherein the thin drug-polymer layer is insoluble in the second polymericsolution; drying the second polymeric solution to form a thin barrierlayer on the first thin drug-polymer layer; and repeating the steps ofdipping the stent framework into the first polymeric solution, dryingthe first polymeric solution, dipping the stent framework into thesecond polymeric solution, and drying the second polymeric solutionuntil a target drug-polymer coating thickness is disposed on the stentframework.
 10. The method of claim 9 wherein the second polymericsolution comprises an anti-proliferative compound.
 11. The method ofclaim 9 wherein the second polymeric solution comprises 5-fluorouracil.